Congestive heart failure (CHF) is a growing clinical problem nationwide. Despite advances in traditional approaches to its treatment, CHF remains a leading cause of morbidity and mortality. A key abnormality at the cellular level in failing hearts is a defect in sarcoplasmic reticulum (SR) function which is associated with abnormal intracellular calcium handing. Failing hearts from humans and animal models have demonstrated a decrease in the expression and activity of the SR Ca2+ATPase (SERCA2a). Recently, we have shown that restoring depressed levels of SERCA2a restores contractility and normalizes intracellular calcium cycling in a rodent model of CHF. We are now extending our experiments to a porcine model of ischemic cardiomyopathy with clinical-grade vectors and delivery systems. Specifically, we will investigate whether (1) overexpression of SERCA2a can improve hemodynamic function in a porcine model of ischemic cardiomyopathy, and (2) long-term overexpression of SERCA2a will induce ventricular and metabolic remodeling without adversely effecting enerqetics in a porcine model of ischemic cardiomyopathy. To answer these questions, we will utilize a porcine model of heart failure where there is depressed LV function and SERCA2a protein levels to examine the response to overexpressing levels of SERCA2a through gene therapy. We will measure hemodynamic function in these animals before and after the delivery of the gene as well as assess the level of SERCA2a expression. We expect to show that gene transfer of SERCA2a to failing porcine hearts will rescue contractility and lead to ventricular and metabolic remodeling. [unreadable] [unreadable]